Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

Abstract

SummaryThe C8’-epimeric pyranosyl amino acid core 2 of amipurimycin was synthesized from D-glucose derived alcohol 3 in 13 steps and 14% overall yield. Thus, the Sharpless asymmetric epoxidation of allyl alcohol 7 followed by trimethyl borate mediated regio-selective oxirane ring opening with azide, afforded azido diol 10. The acid-catalyzed 1,2-acetonide ring opening in 10 concomitantly led to the formation of the pyranose ring skeleton to give 2,7-dioxabicyclo[3.2.1]octane 12. Functional group manipulation in 12 gave 21 that on stereoselective β-glycosylation afforded the pyranosyl thymine nucleoside 2 – a core of amipurimycin.

The Amipurimycin and Miharamycin Biosynthetic Gene Clusters: Unraveling the Origins of 2-Aminopurinyl Peptidyl Nucleoside Antibiotics

“…Miharamycinine (17) was consumed in the presence of Mhr20 only when coincubated with both L-arginine and ATP (Figure 4). The identity of the product was confirmed to be miharamycin B (2) by coelution with the standard compound and high-resolution mass spectrometry.…”

“…Interestingly, while the total synthesis of amipurimycin was accomplished only recently, 16 some 40 years after the initial discovery of this PNA, a successful total synthesis of a miharamycin has yet to be reported. 17,18…”

“…Interestingly, while the total synthesis of amipurimycin was accomplished only recently, 16 some 40 years after the initial discovery of this PNA, a successful total synthesis of a miharamycin has yet to be reported. 17,18 Herein, we identify and characterize the biosynthetic gene clusters of the miharamycins and amipurimycin from S. miharaensis and S. novoguineensis, respectively. The presence of genes encoding characteristic polyketide biosynthetic enzymes along with labeled precursor feeding studies imply that the core saccharides of these PNAs are likely partially polyketide-derived.…”

Identification of the Amipurimycin Gene Cluster Yields Insight into the Biosynthesis of C9 Sugar Nucleoside Antibiotics

“…The structural features, as well as the uncharacterized mechanism of antifungal action, render APM an attractive yet challenging target for synthesis. In the past three decades, various structural fragments and analogues have been synthesized. − However, the true configuration of APM was not resolved until a recent work on total synthesis of eight diastereoisomers, where the authors suggested that the configuration previously assigned at C-3′ should be opposite . The challenges in total synthesis of APM have also raised interest in its biosynthesis.…”

The Miharamycins and Amipurimycin: their Structural Revision and the Total Synthesis of the Latter

“…A chelation‐controlled (anti‐Felkin–Anh) Luche reduction of α‐amino ketone 11 with NaBH 4 /CeCl 3 (MeOH, −30 °C) provided the required 7 S ‐ol 12 in a poor stereoselectivity (dr≈3:1), which was greatly improved when using Zn(BH 4 ) 2 as the reductant (dr=12.4:1) . To our good fortune, conversion of furanoside 12 to fused pyranoside 13 , capable of adopting a twist‐boat conformation, was realized following the previous procedure . Thus, removal of the isopropylidene acetals in 12 (75 % HOAc, 60 °C), protection of the primary 9‐OH with TBDPS, and treatment of the resulting furanose hemiacetal ( B ) with Hf(OTf) 4 (DTBMP, EtOAc, CaSO 4 , 60 °C) afforded 13 in a satisfactory 51 % yield (for 3 steps).…”